Biochemical and pharmacologic studies as well as antitumor testing in murine tumor models are proposed which are directed at the improvement in efficacy of antifol therapy of human cancer, particularly in regard to achieving a broader spectrum of antitumor response. This program is based on recently documented differences in cell membrane transport systems mediating folate analog uptake not only among different tumors, but between tumor- and drug-limiting, normal proliferative tissues. The studies proposed involve the design, synthesis, and evaluation of new analogs of methotrexate. Proposed for study are compounds modified in the C9-N10 bridge and in the glutamate moiety (including analogs of di- and triglutamate), and reduced analogs substituted at N5 and N10. If early results dictate and time permits, certain quinazolines will also be prepared and studied. Development of more effective therapeutic drug combinations incorporating new folate analogs is also proposed.